Circadian oscillations of physiological functions and immune response to infectious agents are two major adaptive control mechanisms involving transcriptional modulation of numerous genes causing multiple and significant physiological effects. Our preliminary data reveal existence of a bi-directional interaction between the circadian regulatory mechanism and responsiveness of an organism to immune challenge mediated via Toll-like receptors. Importantly, we identified major players of the cross- talk connecting the circadian and immune response by demonstrating a physical and functional interaction between the core circadian transcription factors CLOCK and BMAL1 and the major mediator of immune response NFkB. Our preliminary studies support the hypothesis that the circadian histone acetyltransferase activity of CLOCK is a co-activator of NFkB-dependent gene expression, and that NFkB, in turn, directly mediates repression of CLOCK/BMAL1-dependent transcription presumably through posttranslational mechanisms. The proposed program is focused on detailed mechanistic and physiological characterization of the CLOCK/NFkB cross-talk in mouse models and its role in determining inflammatory responses, circadian functions and response to systemic genotoxic stresses known to be influenced by both pathways. The completion of the proposed program will result in defining regulatory rules and molecular mechanisms involved in the cross-talk between two most fundamental systems controlling the organismal interaction with its environment. It will lay the ground for new approaches and reagents for rational pharmacological modulation of inflammation and circadian functions with potential impact to treat or prevent a variety of pathologies.